Parenteral dental local anesthetic solutions containing an alkantheline



surgical field until a blood restricting oral secretions 'tion in dentistry include use United States Patent Allen M. Olinger, Jr., Kentfield, Calif.

No Drawing. Application August 8, 1955 Serial No. 527,147

9 Claims. (Cl. i67-52).

This invention relates to aqueous solutions for parenteral use in dentistry comprising a local anesthetic, an aikantheline, and Water.

It is a primary object of this invention to provide by a single injectable solution a means for producing local anesthesia and at the same time producing a controlled general dryness of the mouth (xerostomia) by a reduction of the salivary and mucous secretions.

Excessive salivation is frequently encountered in dentistry and may become a source of difiiculty, particularly in restorative procedures, that is inlays, amalgams, silicates, etc., and in oral surgery such as the extraction of teeth, root amputations, excision of tumors and cysts, alveolectomy, and pulpotomy. Moisture adversely affects certain dental materials, such as silicate cement, oxyphosphate of zinc, cements, for placing inlays, crowns, bridges, ctc., amalgam and gold foil.

it is beneficial in surgical procedures performed within the oral cavity to limit or restrict saliva from entering the clot has established itself. By a more nearly aseptic field can be maintained and a more favorable environment provided conducive to healing. It is desirable, therefore, both as an aid to the operation to be performed and to alleviate the discomfort and annoyance to the patient caused by excessive salivation, to reduce substantially the serous and mucous secretions. However, in obtaining the drier operative field it is of course important that xerostomia be controlled so as not to produce an excessive .degree or duration of dryness of the mouth.

The presently available means for controlling salivaof various types of saliva ejectors or aspirators, the use of which is frequently accompanied by trauma and annoyance to the patient, rub- .ber dam, which in many dental procedures cannot be successfully used, and cotton rolls which are inadequate. All of these methods consume time and thereby prolong '.the operation. There has also been employed the method of premedication, orally or parenterally, with an anti- -sialagogic drug about one-half to two hours before administration of the local anesthetic; and there has also been used the injection of a mixture of atropine and local anesthetic solutions. The drawbacks of the premedication technique are obvious, since the patient is thereby required to be under medication for a relatively long time, and two separate injections or oral medications are required, with resultant inconvenience to the patient and to the dentist. Moreover, atropine has widespread and manifold actions in the body which prevent obtaining the desired discrete therapeutic eifects without undesirable or unpleasant side-efiects, for example on the respiration, circulation, eyes, body temperature, and skin, in some cases causing tachycardia, hyperthemia, and skin erythema.

I have now succeeded in overcoming the inadequacies and disadvantages of the prior art compositions and procedures for producing xerostcmia for dental procedures by providing compositions comprising an aqueous solution' of an injectable local anesthetic having incorporated therein 1-50 mg. of alkantheline per ml. of the local anesthetic solution.

The local anesthetics useful in my novel compositions are the water-soluble injection local anesthetic agents suitable for use in dentistry. These agents include for example, procaine (Z-diethylaminoethyl p-aminobenzo ate), mixtures of procaine and tetracaine (Z-dimethylaminoethyl p-(n-butylamino)benzoate), butethamine (2- isobutylaminoethyl p-aminobenzoate), propoxycaine (2- dimethylaminoethyl 4 (m-butylamino)-2-(n-propoxy) benzoate, lidocaine (omega-diethylamino-Z,G-dimethylacetanilide), hexylcaine (1-cyclohexylamino-Z-propyl benzoate), and Z-diethylaminoethyl 3-amino-2-(n-butoxy)benzoate. The compounds are of course employed in the form of their water-soluble acid addition salts, ordinarily the hydrochlorides. Usually the concentration of the local anesthetic agent in the aqueous solution is in the range 0.5 to 4% by weight, and most frequently is l2%. Conventionally, these local anesthetic solutions contain a small amount of a vasoconstrictor, such as the hydrochloride or tartrate or other acid addition salt of epinephrine, levo-arterenol, or nordefrin, together with small quantities of salts to render the solutions isotonic, such as sodium chloride, and potassium chloride, and preserving agents, such as sodium bisulfite, calcium disodium ethylenediaminetetraacetate, and methyl paraben.

The alitantheline employed in my novel compositions is a quarternary ammonium salt of an alkamine ester of 9-xanthenecarboxylic acid and has the structural formula lower alkyl 0 1 lower alkyl ll I /COCHz-OH2N\ 6 o I lower alkyl and propantheline which is also readily available as the bromide, which is chemically designated as Z-diisopropylaminoethyl 9-xanthenecarboxylate methobromide and has the structural formula CH(OH3)2 0 (C a)2 A c'i-o-om-om q K C The local anesthetic and the alkantheline can be in corporated into a single aqueous solution by conventional means. Thus, the appropriate respective quantifies of the two solid compounds can be dissolved together in the required amount of Water, with the conventional additive agents present in injection local anesthetic solutions used in dentistry and mentioned hereinabove or, alternatively, the local anesthetic agent and the alkantheline can be dissolved separately and thereafter the aqueous solutions mixed before use to give a single solution; or the local anesthetic solution with its combined agents can be used as the solvent for the crystalline alkantheline.

The amount of the alkantheline employed in my compositions is 1-50 mg. of alkantheline per ml. of the aqueous local anesthetic solution, the preferred range generally being about 1-5 mg. per ml.; employing methantheline, the optimum amount usually is about 2.5 mg. per ml. and, employing propantheline, about 1.0 mg. per ml. The amount of local anesthetic solution employed in each injection in dentistry is about 0.5 ml. to 10 ml., the most frequently used volumes being on the order of 0.5 to 3 ml. per injection. The abovenoted range of concentration of the alkantheline is chosen so as to provide this compound in proper amount, when the usual volume of anesthetic solution is injected, to produce a controlled Xerostomia throughout the dental. procedure, for example, up to several hours duration. Thus, for instance, the addition of 100 mg. of an alkantheline bromide to ml. of a 2% solution of procaine hydrochloride yields a composition of my invention which contains 5.0 mg. of the a kantheline bromide and 20 mg. of procaine hydrochloride per ml. of solution.

It will be appreciated from the foregoing that the compositions of my invention differ from the conventional aqueous local anesthetic solutions employed for injection in dentistry in containing an alkantheline in amount sufiicient to produce a controlled xerostomia during the carrying out of the dental procedure. A particular advantage of my new compositions is that the combination of the alkantheline and the local anesthetic in a single solution provides a satisfactory degree of xerostomia with a much smaller quantity of the alkantheline than that required when the alkantheline is employed in a separate medication, thus allowing the virtual elimination of undesirable side-effects of larger doses of the .alkantheline such as blurring of vision and urinary retention. There is a reduction in the duration of anesthesia, and this effect is distinctly advantageous since anesthesia as produced by the injection local anesthetics is ordinarily prolonged beyond the requirements of most dental procedures. On the other hand, the properties of the local anesthetic agent itself in my compositions are essentially unaffected as to the latency period, stability, profoundness of anesthesia produced, toxicity, and degree of activity.

My new compositions are administered in the conventional manner employed in dentistry for the production of local anesthesia by injection. For example, the injections are submucal: infiltration, mandibular, tuberosity, etc.

My invention is illustrated by the following examples without, however, being restricted thereto.

Example 1 50 mg. of crystalline methantheline bromide was dissolved in ml. of an aqueous solution containing 2% procaine hydrochloride, 0.15% tetracaine hydrochloride, 0.01% nordefrin hydrochloride, 0.2% acetone sodium bisulfite, 0.2% sodium chloride, and 0.4% potassium sulfate. The resulting solution, which contained 1.66 mg. of methantheline bromide per ml., was employed in making injections in dental patients in a dosage of 1 to 6 ml. of the composition per injection. The injections of the solution, which were submucal, included: infiltration, mandibular, tuberosity, greater palatine and mental. The operations included the following: extraction, seat bridge, preparations for inlays, seat crowns, seat inlays,

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preparation for amalgam, amalgam restorations, silicates, gingevectomy, wax pattern, crown preparations, preparation for foil, impressions, and gold foils. In these instances, the composition produced effective local anesthesin and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 2 50 mg. of crystalline methantheline bromide was dissolved in 30 ml. of an aqueous solution containing 2% rocaine hydrochloride, 0.15% tetracaine hydrochloride, 0.0033% levoarterenol bitartrate monohydrate, 0.4% sodium chloride and 0.2% acetone sodium bisulfite. The resulting solution, which contained 1.66 mg. of methantheline bromide per ml., was employed in making injections in dental patients in a dosage of 1 to 3 ml. of the solution per injection. The injections of the solution, which were submucal, included: infiltration, mandibular, tuberosity, greater palatine and mental. The operations included the following: inlays placed, silicates, extraction, amalgams, impressions, foils, preparations for inlays, preparations for amalgams, wax pattern, crowns placed and crown preparations. In these instances, the composition produced effective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patients.

Example 3 mg. of crystalline methantheline bromide was dissolved in 30 ml. of aqueous solution containing 2% procaine hydrochloride, 0.15 tetracaine hydrochloride, 0.0033% levoarterenol bitartrate monohydrate, 0.4% sodium chloride and 0.2% acetone sodium bisulfite. The resulting solution, which contained 3.33 mg. of methantheline bromide per ml., was employed in making injections, in a dosage of 7 ml. of the composition per injection, in a dental patient requiring three extractions. The injections of the solution, which were submucal, included: infiltration, tuberosity, infraorbital, and greater palatine. In these instances, the composition produced effective local anesthesia and controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 4 mg. of crystalline methantheline bromide was dissolved in 30 ml. of an aqueous solution containing 2% procaine hydrochloride, 0.15 tetracaine hydrochloride, 0.0033% levoarterenol bitartrate monohydrate, 0.4% sodium chloride and 0.2% acetone sodium bisulfite. The resulting solution, which contained 5 mg. of methantheline bromide per ml., was employed in a submucal mandibular injection, in a dosage of 2 ml., in a dental patient requiring an amalgam restoration. In this instance, the composition produced effective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 5 50 mg. of crystalline methantheline bromide was dissolved in 30 ml. of an aqueous solution containing 2% procaine hydrochloride, 0.004% epinephrine bitartrate, 0.15% sodium bisulfite, 0.04% potassium chloride, and 0.375% sodium chloride. The composition thus obtained, which contained 1.66 mg. of methantheline bromide per ml. of solution, was employed in making injections in dental patients in a dosage of 0.5 to 2 ml. of the composition per injection. The Operations performed included: foil, inlay preparations, inlays, crown preparations, amalgam, and extraction. In these instances, the composition produced effective local anesthesia and a controlled Xerostomia which was satisfactory to both the dentist and the patient.

Example 6 50 mg. of crystalline methantheline bromide was dissolved in 30 ml. of an aqueous solution containing 2% procaine hydrochloride, 0.4% propoxycaine hydrochloride, 0.0033% levo-arterenol bitartrate monohydrate, 0.3% sodium chloride, and 0.2% acetone sodium bisulfite. The composition thus obtained, which contained 1.66 mg. of methantheline bromide per ml. of solution, was employed in making injections in dental patients in a dosage of l to 4 ml. of the composition per injection. The injections of the composition, which were submucal, included: infiltration, mandibular, tuberosity, and mental. The operations performed included: bridge, extraction, inlay preparations, crowns, inlays, amalgams, amalgam preparations, silicates, wax pattern, crown preparations, impressions, and foils. In these instances, the composition produced elfective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 7 50 mg. of crystalline methantheline bromide was dissolved in 20 ml. of an aqueous solution containing 2% lidocaine hydrochloride, 0.002% epinephrine, 0.6% sodium chloride, 0.5% sodium pyrosulfite, and 1.0% methylparaben. The composition thus obttained, which contained 2.5 mg. of methantheline bromide per ml. of solution, was employed in making injections in dental patients in a dosage of 0.5 to 8 ml. of the composition per injection. The injections of the composition, which were submucal, included: infiltration, mandibular, tuberosity, infraorbital, greater palatine and mental. The operations performed included: silicates, amalgams, inlay preparations, inlays, foils, crown preparations, impressions, crowns, extractions, wax patterns, bridges, amalgam preparations, foil preparations, gingevectomy, and section for biopsy. In these instances, the composition produced elfective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 8 100 mg. of crystalline methantheline bromide was dissolved in 20 ml. of an aqueous solution containing 2% lidocaine hydrochloride, 0.002% epinephrine, 0.6% sodium chloride, 0.05% sodium pyrosulfite, and 1.0% methylparaben. The composition thus obtained, which contained 5 mg. of methantheline bromide per ml. of solution, was employed in a dosage of 2 ml. in making an injection in a dental patient requiring an inlay preparation. In this instance, the composition produced effective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 9 50 mg. of crystalline methantheline bromide was dissolved in 20 ml. of an aqueous solution containing 2% lidocaine hydrochloride and levo-arterenol 130,000. The composition thus obtained, which contained 2.5 mg. of methantheline bromide per ml. of solution, was employed in making injections in dental patients in a dosage of 0.5 to 2 ml. of the composition per injection. The injections of the composition, which were submucal, included: infiltration, mandibular, tuberosity, and mental. The operations performed included: crown preparations, inlay preparations, amalgams, crown, silicates, and inlays. In these instances, the composition produced effective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 10 50 mg. of crystalline methantheline bromide was dissolved in 20 ml. of an aqueous solution containing 2% lidocaine hydrochloride, 0.001% epinephrine, 0.6% sodium chloride, 0.05% sodium pyrosulfite, and 1.0% methylparaben. The composition thus obtained, which contained 2.5 mg. of methantheline bromide per ml. of solution, was employed in making injections in dental greater alatine,

Example 11 50 mg. of crystalline methantheline bromide was dissolved in 30 ml. of an aqueous solution containing 1% hexylcaine hydrochloride. The composition thus obtained, which contained 1.66 mg. of methantheline bromide per ml. of solution, Was employed in making injections in dental patients in a dosage of 1 to 2 ml. of the composition per injection. The injections or" the composition, which were submucal, included: infiltration, mandibular, tuberosity, and mental. The operations performed included: impression, foils, crown preparation, amalgams, silicates, inlays, extraction and inlay preparation. In these instances, the composition produced effective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 12 30 mg. of crystalline propantheline bromide was dissolved in 30 ml. of an aqueous solution containing 2% procaine hydrochloride, 0.4% propoxycaine hydrochloride, 0.0033% levo-arterenol bitartrate monohydrate, 0.3% sodium chloride, and 0.2% acetone sodium bisul fite. The composition thus obtained, which contained 1.0 mg. of propantheline bromide per ml. of solution, was employed in making injections in dental patients in a dosage of 0.5 to 3.0 ml. of the composition per injection. The injections of the composition, which were submucal, included: infiltration, greater palatine, mandibular, and tuberosity. The operations performed included: amalgams, silicates, preparations for inlays, seat inlays, seat crown, and seat bridge. In these instances, the composition produced effective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 13 30 mg. of crystalline propantheline bromide was dissolved in 30 ml. of an aqueous solution containing 2% procaine hydrochloride, 0.15% tetracaine hydrochloride, 0.01% nordefrin hydrochloride, 0.2% sodium chloride, and 0.4% potassium sulfate. The resulting composition, which contained 1 mg. of propantheline bromide per ml. of solution was employed in making injections in dental patients in a dosage of 1 to 3 ml. of the composition per. injection. The injections of the composition, which were submucal included: infiltration, mental, mandibular, and tuberosity. The operations performed included: inlay preparations, crown preparations, amalgams, silicates, wax patterns, seat inlays, and extractions. In these instances, the composition produced effective local anesthesia and a controlled xerostomia which was satisfactory to both the dentist and the patient.

Example 14 When 20 mg. of crystalline propantheline bromide is substituted for the methantheline bromide in preparing the solution disclosed hereinabove in Example 7, there is obtained a composition containing 1 mg. of propantheline bromide perml. of solution, and when this composition is used in dosages of 1 to 3 ml. as an injection local anesthetic in dental operations, there is produced effective local anesthesia and a satisfactory controlled xerostomia,

I claim:

1. An aqueous composition suitable for parenteral injection for the production of local anesthesia and controlled xerostomia in the oral cavity which comprises an aqueous solution of an injection dental local anesthetic in anesthetizing concentration, a small amount of a vasoconstrictor, and an alkantheline in the amount of 1-50 mg. per ml. of the said solution. 7

2. The composition of claim 1 wherein the alkantheline is methantheline.

3. The composition of claim 1 wherein the alkantheline is propantheline.

4. An aqueous composition suitable for parenteral injection for the production of local anesthesia and controlled xerostomia in the oral cavity which comprises an aqueous solution of procaine in anesthetizing concentration, a small amount of a vasoconstrictor, and methantheline in the amount of 1-50 mg. per ml. of the said solution.

5. An aqueous composition suitable for parenteral injection for the production of local anesthesia and controlled xerostornia in the oral cavity which comprises an aqueous solution of procaine in anesthetizing concentration, a small amount of a vasoconstrictor, and propantheline in the amount of 1-30 mg. per ml. of the said solution.

6. An aqueous composition suitable for parenteral injection for the production of local anesthesia and controlled xerostomia in the oral cavity which comprises an aqueous solution of lidocaine in anesthetizing concentration, a small amount of a vasoconstrictor, and methantheline in the amount of 1-50 mg. per ml. of the said solution.

7. An aqueous composition suitable for parenteral injection for the production of local anesthesia and con- Percent Propoxycaine hydrochloride 0.4 Procaine hydrochloride 2.0

Levo-arterenol bitartrate monohydrate 0.0033 Methsmtheline bromide 0.166

9. An aqueous composition suitable for parenteral injection for the production of local anesthesia and controlled Xerostomia in the oral cavity which comprises an aqueous solution of procaine in anesthetizing concentration and methantheline in the amount of 1-5 mg. per ml. of the said solution.

References Cited in the file of this patent UNITED STATES PATENTS 1,656,784 Fischer Ian. 17, 1928 OTHER REFERENCES Merck Index, 6th ed., 1952, Merck and Co., Rahway, N. 1., pp. 624.

Modern Drug Encyclopedia and T her. Index, 5th ed., 1952, Drug. PubL, Inc., N. Y., pp. 84, 93, 94, 789-791.

Drill: Pharmacology in Medicine, McGraw-Hill, N. Y., 1954, pp 9/7 and 42/12-42/16.

U. 5. DEPARTMENT OF COMMERCE PATENT OFFICE CERTIFICATE 0F CQRREC TION Patent No. 2,830,930 April. 15, 1958 Allen M, Clinger, Jr,

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letter$ Patent should read as oorrected below.

Column 45 linelZ, for "levoarterenol" read levo=arterenol line 30, for of aqueous" read of an aqueous line 33, for "levoarterenol" read levo=arterenol line 41, for "and Controlled." read and a controlled line 4'7, for LeVOarterenOl" read levo-= arterenol column 5, line-22, for "005%" read OO57 line 23, for "obttained" read obtained column 8, line 20, after the syllable. "tion" insert -=-,a small amount of a vasoeonstrictor,

Signed and sealed this 20th day of Ma 19580 (SEAL) Attest:

KARL Ho AXLINE ROBERT c. WATS( Attesting Officer Comnissioner of Pater! 

1. AN AQUEOUS COMPOSITION SUITABLE FOR PARENTIAL INJECTION FOR THE PRODUCTION OF LOCAL ANESTHESIA AND CONTROLLED XEROSTOMIA IN THE ORAL CAVITY WHICH COMPRISES AN AQUEOUS SOLUTION OF AN INJECTION DENTAL LOCAL ANESTHETIC IN ANESTHETIZING CONCENTRATION, A SSMALL AMOUNT OF A VASOCONSTRICTOR, AND AN ALKANTHELINE IN THE AMOUNT OF 1-50 MG. PER ML. OF THE SAID SOLUTION. 